[Downloaded free from http://www.sjkdt.org on Thursday, October 5, 2017, IP: 36.84.1.

53]

Saudi J Kidney Dis Transpl 2016;27(1):67-72

2016 Saudi Center for Organ Transplantation Saudi Journal
of Kidney Diseases
and Transplantation

Original Article

The Predictive Factors for Relapses in Children with Steroid-Sensitive

Nephrotic Syndrome
Shatha Hussain Ali1, Abdulkareem Mohammed Ali1, Abbas Hindi Najim2
1
Department of Pediatrics, College of Medicine, AlNahrain University,
2
AlKadhymia Teaching Hospital, Baghdad, Iraq

ABSTRACT. Most patients with steroid-sensitive nephrotic syndrome (SSNS) have frequent
relapses (FR); this is considered one of the main problems because of its association with a high
incidence of complications. The aim of our study was to evaluate the different factors that might
be associated with the occurrence of relapse in SSNS. This is a retrospective study of 80 patients
with SSNS conducted at the Pediatric Nephrology Clinic in the Al-Kadhymia Teaching Hospital
between January 2011 and November 2011. The study patients were divided into two groups: FR
and infrequent relapses (IFR). The age of the study patients was between one and 14 years; 45
patients had FR (56.3%) and 35 patients had IFR (43.7%). Males constituted 55 patients (68.7%)
and 25 patients were female (31.3%). The incidence of FR was high in all age-groups, except in
the 15 years age-group, and was higher in children living in urban areas. There was no
significant difference between the two groups in age, gender, place of residence and renal
functions. However, there was a significant difference in the presence of hematuria, time taken to
respond to therapy and duration of steroid therapy required; all were higher in the FR group. Our
results will help clinicians in identifying possible FR such that they may be monitored closely.

Introduction g/24-h in adult, 40 mg/m2/h in children), hypo-

Nephrotic syndrome (NS) is primarily a pe-
diatric disorder and is 15-times more common
in children than in adults. The reported inci-
dence of NS is 23/100,000 children per year.1
It is characterized by heavy proteinuria (>3.5
Correspondence to:
Dr. Shatha Hussain Ali
Department of Pediatrics, College of Medicine,
Al Nahrain University,
P. O. Box 70074, Baghdad, Iraq
E-mail: shathah666@yahoo.com
albuminemia <2.5 g/dL, edema and hyper-
lipidemia.1-3 NS is classified into the following:
congenital NS, idiopathic NS and secondary
NS.2,4,5
The majority of affected children have
steroid-sensitive minimal change disease
(MCD).2,3 Renal biopsy is recommended for
those patients who do not respond to ste-
roids.3,6 The majority of children with NS re-
lapse within the first six months of initial
therapy. Approximately 30% of children expe-
rience only one attack and get cured after a
single course of steroids. The peak age of
[Downloaded free from http://www.sjkdt.org on Thursday, October 5, 2017, IP: 36.84.1.53]
68
onset of NS is between 18 months and six
years and the male to female ratio is 2:1.7
Aim of the study
This study was conducted to determine the
fre-quency of relapses in children with steroid-
sensitive NS (SSNS), and included demogra-
phic factors such as age, gender and place of
residence as predictive factors of occurrence of
relapses in SSNS. We also aimed to study the
relationship between the presence of hematuria
and renal function at initial presentation with
occurrence of relapses in SSNS as well as to
study the relationship between the time taken
to respond to steroid therapy and the duration
of steroid therapy of the initial attack and
occurrence of subsequent relapses in SSNS.
Patients and Methods
This is a retrospective study of 80 patients
with SSNS with an age-range of one to 14
years who were diagnosed, treated and fol-
lowed-up for at least one year in the Pediatric
Nephrology Clinic of the Al-Kadhymia
Teaching Hospital. The study was conducted
from January to November 2011.
Diagnosis of NS was made according to the
following criteria: heavy proteinuria >40
mg/h/m2 (for older children with collected 24-
h urine); or protein/creatinine ratio >0.2
g/mmol, Albustix +++ (for non-toilet-trained
children or difficult collection of 24-h urine),
hypo-albuminemia <2.5 g/dL or edema and
hyper-lipidemia with total cholesterol of 170
200 mg/dL.1-3
Steroid-responsive NS was defined as pa-
tients achieving complete remission with ste-
roid therapy for four weeks.1-3 Steroid-resistant
NS was defined as failure to achieve remission
following four weeks of treatment with pred-
nisone 60 mg/m2.1-3 Hematuria was defined as
the presence of at least five red blood cells per
microliter of urine.1-3
Reference values for normal blood urea was
40 mg/dL and for serum creatinine were 0.3
0.7 mg/dL for children and 0.51 mg/dL for
adolescents.1-3
Ali SH, Ali AM, Najim AH
Treatment at the Pediatric Nephrology Unit
was according to the protocol of the Interna-
tional Society for Kidney Disease in Children
(ISKDC).1-3 For the initial attack, the treatment
protocol consisted of prednisone 60 mg/m2/
day in divided doses for four weeks followed
by 40 mg/m2/day in divided doses. This was
followed by alternate-day therapy for four
more weeks, which was tapered thereafter.
Relapse was treated with prednisone in a
dose of 60 mg/m2/day, which was continued
for three days after the urine became protein-
free, followed by alternate-day prednisone 40
mg/m2 for four weeks.
The following data were taken from the
record files of the patients: age at presentation,
gender, place of residence, hematuria at initial
presentation, renal function (B. urea, S. crea-
tinine), time needed to respond to steroid the-
rapy, duration of steroid therapy and number
of relapses.
The exclusion criteria included patients with
incomplete data at initial presentation, those
who were followed-up for <12 months and
those who had steroid-resistant NS and those
with congenital NS.
Accordingly, the study patients were divided
into two groups:1-3
a) Infrequent relapses (IFR): less than two
relapses within six months of the initial
response or less than four relapses for any
year thereafter.
b) Frequent relapses (FR): two or more re-
lapses within six months of initial res-
ponse or four or more relapses within a
period of one year.
The data were analyzed by comparing pa-
tients with FR and IFR regarding age and sex,
place of residence, presence of hematuria,
renal function (B. urea and S. creatinine), time
needed to respond to steroid therapy and dura-
tion of maintenance steroid therapy.
No Institutional Ethics Committee clearance
was sought because the work performed was
the usual investigations and treatment.
Statistical analysis
Data collected were analyzed using available
[Downloaded free from http://www.sjkdt.org on Thursday, October 5, 2017, IP: 36.84.1.53]

Relapses in children with steroid sensitive nephrotic syndrome 69

Table 1. Correlation of relapses in children with nephrotic syndrome by gender, age and place of
residence.
Study groups
Infrequent relapse (n = 35) Frequent relapse (n = 45)
Gender No. (%) No. (%)
Male 28 (80) 27 (60.0)
Female 7 (20) 18 (40.0)
P-value 0.104
Age-groups No. (%) No. (%)
15 years 24 (68.6) 27 (60.0)
>510 years 9 (25.7) 14 (31.1)
>10 years 2 (5.7) 4 (8.9)
P-value 0.708
Place of residence No. (%) No. (%)
Rural 15 (42.9) 21 (46.7)
Urban 20 (57.1) 24 (53.3)
P-value 0.734

statistical software package, SPSS version to the following:

10:00. The data are presented as simple mea-
sures of number or percentage using the Chi-
square test. For testing the statistical signi-
ficance of difference between the different
parameters, the number and percentage with
use of probability value are presented. P-value
<0.05 was considered significant.
Results
A total of 80 children with SSNS were inclu-
ded in this study. Of them, 45 patients had FR
(56.3%) and 35 patients had IFR (43.7%).
Males constituted 55 of all patients (68.7%)
and 25 patients were female (31.3%); the male
to female ratio was 2.2:1.
The most common age-group at presentation
was 15 years, comprising a total of 51 pa-
tients (63.7%).
The duration of follow-up ranged from 12 to
72 months, with a mean of 24.7 13.79
months (SD).
The two groups were compared with relation
Table 2. Correlation of relapse in patients with nephrotic syndrome with the presence of hematuria at
onset.
Study groups
Infrequent relapse (n = 35)
Hematuria No. (%)
Yes 2 (5.7)
No 33 (94.3)
P-value 0.008
Gender
The incidence of FR was higher in females
compared with males; the difference was not
statistically significant (P-value = 0.104; Table
1).
Age
The incidence of FR was high in all age-
groups, except in the 15 years age-group; there
were 24 IFR (68.6%) and 27 FR (60%) in this
age-group and the difference was not statis-
tically significant (P-value = 0.708; Table 1).
Place of residence
FR were more common in children living in
urban regions (n = 24, 53.3%) than in those
living in rural regions (n = 21, 46.7%);
however, there was no statistically significant
difference (P-value = 0.734; Table 1).
Hematuria
A total of 15 patients presented with hematuria;
Frequent relapse (n = 45)
No. (%)
13 (28.9)
32 71.1)
[Downloaded free from http://www.sjkdt.org on Thursday, October 5, 2017, IP: 36.84.1.53]

70 Ali SH, Ali AM, Najim AH

Table 3. Correlation of relapses in patients with nephrotic syndrome with time needed to respond to
steroid therapy and duration of maintenance steroid therapy.
Study groups
Infrequent relapse (n = 35) Frequent relapse (n = 45)
No. (%) No. (%)
Time for response
2 weeks 33 (94.3) 21 (46.7)
24 weeks 2 (5.7) 23 (51.1)
48 weeks 0 (0.0) 1 (2.2)
P-value 0.001
Duration of treatment
2 months 9 (25.7) 15 (33.3)
23 months 11 (31.4) 18 (40)
36 months 15 (42.9) 12 (26.7)
P-value 0.392

13 of them had FR (28.9%) while two had IFR tion parameters and there was no statistically
(5.7%). The difference was statistically sig- significant difference between the two groups
nificant (P-value = 0.008; Table 2). as shown in Table 4.

Time needed to respond to steroid therapy Discussion

Majority of patients with IFR (n = 33, 94.3%)
responded to steroid therapy in <2 weeks, This study showed a predominance of male
while most patients with FR (n = 23, 51.1%) patients over females, and the result was simi-
showed response to steroids within two to four lar to studies elsewhere.2,7-13 The most com-
weeks. A statistically significant difference mon age-group at presentation was 15 years,
was found, with a P-value of 0.001 (Table 3). which was also noticed in previous studies
from different regions.10-14
Duration of maintenance steroid therapy In our study, 56.3% of patients had FR,
More patients with IFR (n = 15, 42.9%) were which is higher than the prevalence of IFR
treated with a longer duration of steroid the- (43.7%); similar findings have been reported
rapy for three to six months, while patients by Esfahani et al,7 Anderson et al,13 Constan-
with FR (n = 12, 26.7%) required treatment for tinescu et al15 and Batrice et al.16
shorter periods of time (Table 3). In agreement with previous studies per-
formed by Constantinescu et al,15 Shuichiro et
Renal function test al17 and Takeda et al,18 we did not find any
Majority of patients in both the IFR and the correlation between age at presentation and
FR group recorded normal values of renal func- future relapses among patients with NS. On
Table 4. Correlation of relapses in patients with nephrotic syndrome with renal function: blood urea and
serum creatinine.
Study groups
Infrequent relapse (n = 35) Frequent relapse (n = 45)
No. (%) No. (%)
Blood urea
40 mg/dL 33 (94.3) 42 (93.3)
>40 mg/dL 2 (5.7) 3 (6.7)
P-value 0.861
Serum creatinine
Normal 34 (97.1) 43 (95.6)
Elevated for age-range 1 (2.9) 2 (4.4)
P-value 0.711
[Downloaded free from http://www.sjkdt.org on Thursday, October 5, 2017, IP: 36.84.1.53]
Relapses in children with steroid sensitive nephrotic syndrome
the other hand, Anderson et al,13 and Sarker et
al19 found a significant correlation between
age at presentation <4 years and <5 years,
respectively, and an increased incidence of
relapses in the future.
A recent study from India found that patients
with FR were younger at onset of the disease,
and the frequency of relapses declined with
increasing age.20 This discrepancy may be
related to the racial differences in the study
population of different studies as well as the
different patterns of idiopathic NS in the
various ethnic groups.13
Several studies have reported a negative
correlation between gender and FR.15,17-20
Anderson et al13 reported that male gender was
associated with a higher risk of steroid depen-
dency and FR despite the prolongation of the
steroid course. Another study found that male
gender is a predictive factor for FR.21
In our study, FR were more common among
patients living in urban than in rural regions.
This finding is in contrast to Sarker et al, who
reported a significantly higher incidence of FR
in rural children than in urban children (P
<0.05).19 Their explanation for this observa-
tion was the delay in the initiation of specific
treatment in rural areas.
An interesting finding in this study was the
relationship between the presence of hematuria
at initial presentation and future relapse. This
association was highlighted by several
studies.15,19,21 Jei-wen et al22 reported a preva-
lence of hematuria at initial presentation of
28% in a group of 50 children with NS aged
>8 years. A recent Indian study recorded that
the presence of hematuria was independently
associated with late steroid resistance.20
Another interesting finding in this study was
a statistically significant association between
early response to steroid therapy and increased
incidence of IFR in patients with SSNS.
Shuichiro et al reported that patients who
responded within eight days of initial steroid
therapy showed a favorable clinical course,
while those with a delayed response (9 or
more days) had a steroid-dependent course.17
This finding was highlighted by Yap et al,
who reported that initial duration of remission
71
of nine days or longer was significantly asso-
ciated with steroid dependency in 91 Asian
children with SSNS.23 Also, Constantinescu et
al recorded that there was a tendency for
patients who took a longer time to respond to
be FR or were steroid dependent. However,
this was significant only among patients with-
out hematuria, because those with hematuria
had similar chances of being IFR or FR/steroid
dependency.15
Two previous studies performed by Constan-
tinescu et al15 and Trompeter et al24 reported
less-frequent relapses among their studied
patients in relation to a longer duration of
steroid therapy, but these results were statis-
tically not significant; their findings were
similar to ours.
On the other hand, Anderson et al.13 found a
significant relationship between prolonged
steroid therapy (>12 weeks) and reduction in
relapse frequency.
In conclusion, our study suggests that FR was
more frequently recorded than IFR among
children with SSNS; there was a male pre-
dominance and the peak age of occurrence of
NS was 15 years. There was a significant cor-
relation between early response to steroid the-
rapy and IFR, while the presence of hematuria
at initial presentation correlated significantly
with FR. These data will help in the early
identification of children with FR and thus
enable proper care.
References
1. Feehally J, Johnson RJ. Introduction to glome-
rular disease. In: Johhnson RJ, Freehally J, eds.
Comprehensive Clinical Nephrology. 1st ed.
Philadelphia: Mosby; 2000. p. 21.1-21.9.
2. Vogt BA, Avner ED. Condition particularly
associated with proteinuria. In: Kliegman RM,
Behrman RE, Jenson HB, Stanton BF, eds.
Nelson Text Book of Pediatrics. 19th ed., Vol.
527. Philadelphia: Saunders; 2007. p. 2190-5.
3. Niaudet P. Steroid sensitive idiopathic neph-
rotic syndrome & steroid resistance idiopathic
nephrotic syndrome in children. In: Avner ED,
Harmon WE, Niaudet P, eds. Pediatric
Nephrology. 6th ed., Vol. 27, 28. Philadelphia:
Lippincott Williams & Wilkins; 2004. p. 543-67.
[Downloaded free from http://www.sjkdt.org on Thursday, October 5, 2017, IP: 36.84.1.53]
72
4. El-Najjar M. Urinary system. In: Pediatic
Clinical Diagnosis. 5th ed., Vol. 9. Egypt: Al-
Ahram Commercial Press, Kalyoub; 2005. p.
314.
5. Watson AR, Tayler CM, Graw MM. Disorders
of urinary system. In: Mctntosh N, Helms PJ,
Smyth RL, eds. Farfar & Arneil's Text Book of
Pediatric. 16th ed., Vol. 16. Philadelphia:
Churchill Livingston; 2003. p. 633-4.
6. Marino BS, Fine KS. Nephrotic Syndrome.
Blueprints. 4th ed., Vol. 14. Philadelphia:
Lippincott Williams & Wilkins; 2007. p. 232.
7. Esfahani ST, Madani A, Asgharian F, et al.
Clinical course and outcome of children with
steroid-sensitive nephrotic syndrome. Pediatr
Nephrol 2011;26:1089-93.
8. Kabuki N, Okugawa T, Hayakawa H,
Tomizawa S, Kasahara T, Uchiyama M.
Influence of age at onset on the outcome of
steroid-sensitive nephrotic syndrome. Pediatr
Nephrol 1998;12:467-70.
9. Eddy AA, Symons JM. Nephrotic syndrome in
childhood. Lancet 2003;362:629-39.
10. Wong W. Idiopathic nephrotic syndrome in
New Zealand children, demographic, clinical
features, initial management and outcome after
twelve-month follow-up: Results of a three-
year national surveillance study. J Paediatr
Child Health 2007;43:337-41.
11. Reshi AR, Bhat MA, Najar MS, et al.
Etiological profile of nephrotic syndrome in
Kashmir. Indian J Nephrol 2008;18:9-12.
12. Rth EM, Kemper MJ, Leumann EP, Laube
GF, Neuhaus TJ. Children with steroid-
sensitive nephrotic syndrome come of age:
Long-term outcome. J Pediatr 2005;147:202-7.
13. Andersen RF, Thrane N, Noergaard K, Rytter
L, Jespersen B, Rittig S. Early age at debut is a
predictor of steroid-dependent and frequent
relapsing nephrotic syndrome. Pediatr Nephrol
2010;25:1299-304.
14. Anochie I, Eke F, Okpere A. Childhood neph-
rotic syndrome: Change in pattern and res-
Ali SH, Ali AM, Najim AH
ponse to steroids. J Natl Med Assoc 2006;98:
1977-81.
15. Constantinescu AR, Shah HB, Foote EF,
Weiss LS. Predicting first-year relapses in
children with nephrotic syndrome. Pediatrics
2000;105(3 Pt 1):492-5.
16. Letavernier B, Letavernier E, Leroy S, Baudet-
Bonneville V, Bensman A, Ulinski T. Predic-
tion of high-degree steroid dependency in pe-
diatric idiopathic nephrotic syndrome. Pediatr
Nephrol 2008;23:2221-6.
17. Fujinaga S, Daishi H, Naoto N. Early identi-
fication of steroid dependency in Japanese
children with steroid-sensitive nephrotic syn-
drome undergoing short-term initial steroid
therapy. Pediatr Nephrol 2010;25:1299-304.
18. Takeda A, Takimoto H, Mizusawa Y, Simoda
M. Prediction of subsequent relapse in children
with steroid-sensitive nephrotic syndrome.
Pediatr Nephrol 2001;16:888-93.
19. Sarker MN, Islam MM, Saad T, et al. Risk
factor for relapse in childhood nephrotic
syndrome A Hospital Based Retrospective
Study. Faridpur Med Coll J 2012;7:18-22.
20. Sinha A, Hari P, Sharma PK, et al. Disease
course in steroid sensitive nephrotic syndrome.
Indian Pediatr 2012;49:881-7.
21. Noer MS. Predictors of relapse in steroid-
sensitive nephrotic syndrome. Southeast Asian
J Trop Med Public Health 2005;36:1313-20.
22. Chang JW, Tsai HL, Wang HH, Yang LY.
Clinicopathological features and prognosis of
Chinese children with idiopathic nephrotic
syndrome between different age groups. Eur J
Pediatr 2009;168:1189-94.
23. Yap HK, Han EJ, Heng CK, Gong WK. Risk
factors for steroid dependency in children with
idiopathic nephrotic syndrome. Pediatr
Nephrol 2001;16:1049-52.
24. Abeyagunawardena AS, Hindmarsh P,
Trompeter RS. Adrenocortical suppression
increases the risk of relapse in nephrotic
syndrome. Arch Dis Child 2007;92:585-8.